7-117642437-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000492.4(CFTR):​c.3718-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

CFTR
NM_000492.4 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.39
Variant links:
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035111412 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of -28, new splice context is: atggtacctatatgtcacAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117642437-G-C is Pathogenic according to our data. Variant chr7-117642437-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2443046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.3718-1G>C splice_acceptor_variant, intron_variant Intron 22 of 26 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.3718-1G>C splice_acceptor_variant, intron_variant Intron 22 of 26 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:1
Dec 27, 2022
Johns Hopkins Genomics, Johns Hopkins University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This CFTR canonical splice site variant is absent from a large population dataset and has not been reported in ClinVar nor the literature, to our knowledge. This variant alters a canonical splice acceptor site and is predicted to cause abnormal gene splicing. We consider CFTR c.3718-1G>C to be pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Jan 12, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
29
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
1.0
D
GERP RS
4.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.98
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-117282491; API